Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by variable and diverse symptoms including the classic triad of hemolytic anemia, thrombosis, and bone marrow failure. It is a disorder primarily seen in the adult population. The authors report a unique case of an 8-year-old girl diagnosed with PNH after initially presenting with a febrile illness and acute kidney injury. …

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by variable and diverse symptoms including the classic triad of hemolytic anemia, thrombosis, and bone marrow failure. It is a disorder primarily seen in the adult population. The authors report a unique case of an 8-year-old girl diagnosed with PNH after initially presenting with a febrile illness and acute kidney injury. Though rare in children, PNH should remain in the differential diagnosis of a child presenting with acute kidney injury. The disease has serious long-term complications, mandating timely diagnosis and appropriate therapy.

Emerging evidence suggests that activation of the complement system is critical in the pathogenesis of the novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 related lung injury. Inhibition of the terminal complement pathway by targeting complement protein 5 (C5) may be an effective therapeutic intervention in CoV-mediated disease.1 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare…

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Emerging evidence suggests that activation of the complement system is critical in the pathogenesis of the novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 related lung injury. Inhibition of the terminal complement pathway by targeting complement protein 5 (C5) may be an effective therapeutic intervention in CoV-mediated disease.1 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell (HSC) disease characterized by intravascular haemolysis, increased thromboembolic risk and bone marrow failure.2.

CONCLUSIONS: PNH should be considered during differential diagnosis among patients with idiopathic PVT. Small PNH clones can be detected in PVT patients that we cannot clearly determine its relationship with PVT. We need furthermore studies to explore the potential role of this finding.

Some patients with pancytopenia do not conform to any diagnostic criteria of known hematological or nonhematological diseases; however, they respond well to corticosteroid, high-dose intravenous immunoglobulin and rituximab treatment. This abnormality is termed immunorelated pancytopenia (IRP). Later studies indicated that IRP might be a kind of autoimmune disease in which T helper (Th) type 2 ce…

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Some patients with pancytopenia do not conform to any diagnostic criteria of known hematological or nonhematological diseases; however, they respond well to corticosteroid, high-dose intravenous immunoglobulin and rituximab treatment. This abnormality is termed immunorelated pancytopenia (IRP). Later studies indicated that IRP might be a kind of autoimmune disease in which T helper (Th) type 2 cell function is enhanced, resulting in the hyperfunction of B lymphocytes, which then produce excess autoantibodies that attack the bone marrow (BM) and cause cytopenia. Hypofunction of regulatory T (Treg) cells and enhanced Th17 cell function, an elevated percentage of plasmacytoid dendritic cells (pDCs) and a decreased percentage of natural killer (NK) cells help to promote the process. Moreover, increased expression of a synergistic stimulator of B lymphocytes, CD70, and the reactive overexpression of the BCR inhibitory coreceptor CD22 also support this claim. Candidate autoantigens targeted by autoantibodies on hematopoietic cell membranes have also been reported in IRP. This review is focused on studies that demonstrate the role of immune responses in the pathogenesis of IRP. Current diagnostic criteria and treatments for IRP are also referenced to provide a thorough understanding. Distinguishing IRP from idiopathic cytopenias of undetermined significance (ICUS) and other hematological disorders, e.g., myelodysplastic syndrome (MDS), aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and Evans syndrome, may help patients with pancytopenia benefit from proper treatment. Further studies are required to achieve new insight into the pathophysiology of IRP with regard to the immune system, which will be instrumental for the development of novel therapies for inhibiting disease initiation and/or progression.

CONCLUSIONS: This simple two-color evaluation of FLAER-negative neutrophils is a highly effective screening test for PNH. Although this approach is not intended to replace the multicolor diagnostic procedure, it could minimize the number of patients requiring a conventional multicolor flow cytometric assay.

Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are pathogenically related non-malignant bone marrow failure disorders linked to T-cell mediated autoimmunity and associated with an increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately 15-20% of AA patients and 2-6% of PNH patients go on to develop secondary MDS/AML by ten years of follow-up. Factors determining an individual patient's risk of malignant transformation remain poorly defined. Recent studies identified nearly ubiquitous clonal hematopoiesis (CH) in AA patients. Similarly, CH with additional, non-PIGA, somatic alterations occurs in the majority of patients with PNH. Factors associated with progression to secondary MDS/AML include longer duration of disease, increased telomere attrition, presence of adverse prognostic mutations and multiple mutations, particularly when occurring early in the disease course and at a high allelic burden. Here, we will review the prevalence and characteristics of somatic alterations in AA and PNH and will explore their prognostic significance and mechanisms of clonal selection. We will then discuss the available data on post-AA and post-PNH progression to secondary MDS/AML and provide practical guidance for approaching patients with PNH and AA who have CH.

Membrane attack complexes (MACs; C5b-9) assembled after complement activation can directly injure self-tissues, leading to various diseases. Eculizumab, a monoclonal antibody (mAb) against complement component C5, is being used in the clinic to treat diseases in which MAC-mediated tissue damage is a primary cause. However, C5 is not a selective target for MAC assembly inhibition, and some patient…

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Membrane attack complexes (MACs; C5b-9) assembled after complement activation can directly injure self-tissues, leading to various diseases. Eculizumab, a monoclonal antibody (mAb) against complement component C5, is being used in the clinic to treat diseases in which MAC-mediated tissue damage is a primary cause. However, C5 is not a selective target for MAC assembly inhibition, and some patients respond incompletely or not at all to the eculizumab treatment. Therefore, C6, the next essential component in the terminal pathway of complement activation, may be an alternative target for the selective inhibition of MAC formation. Surprisingly, few reports describe a functional blockade of C6 using a specific mAb. Here, we report the development of an anti-human C6 mAb (clone 1C9) that recognizes C6 both in free circulation and within C5b6 complexes. This mAb blocked C7 binding to C5b6 complexes and consequently inhibited MAC formation and protected affected paroxysmal nocturnal hemoglobinuria patient red blood cells from MAC-mediated damage in vitro. In addition, this mAb cross-reacts with rhesus monkey but not mouse complement C6. Finally, 1C9 significantly reduced human complement-mediated intravascular hemolysis in vivo in a mouse model. These results suggest that the anti-C6 mAb holds promise as a new therapeutic agent that selectively targets MAC for many complement-mediated pathological conditions.

Transcatheter mitral valve replacement (TMVR) is emerging as an alternative treatment strategy to surgery for patients with severe mitral annular calcification (MAC) who are not candidates for traditional mitral valve surgery. Paravalvular leak (PVL) is common following TMVR for severe MAC and can lead to heart failure symptoms and/or intravascular hemolysis, the latter of which usually is clinic…

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Transcatheter mitral valve replacement (TMVR) is emerging as an alternative treatment strategy to surgery for patients with severe mitral annular calcification (MAC) who are not candidates for traditional mitral valve surgery. Paravalvular leak (PVL) is common following TMVR for severe MAC and can lead to heart failure symptoms and/or intravascular hemolysis, the latter of which usually is clinically stable. We report the case of a 67-year-old woman with symptomatic severe aortic stenosis and mitral stenosis with MAC in the setting of prior chest irradiation who was treated initially with transcatheter aortic valve replacement followed by TMVR at a later date (Sapien S3 system; Edwards Lifesciences). Immediately following TMVR, she developed acute profound hemolysis which manifested with hemoglobinuria, transfusion-dependent anemia, and acute renal failure requiring renal replacement therapy. She was treated with post-dilation balloon valvuloplasty after failed transcatheter PVL closure 10 days following TMVR with resulting improvement in the PVL. The hemolytic anemia resolved and renal function recovered without the need for continued hemodialysis 2 months later and stabilization of glomerular filtration rate at 6 months. This case highlights a potential severe complication of TMVR in MAC and suggests that improvement in hemolysis and late recovery of renal function may occur following treatment of PVL.

CONCLUSIONS: The detection of PIGA mutations and additional variants by targeted NGS not only shed light on the genetic characteristics of PNH, but also provided an important reference value in the diagnosis of PNH at molecular level.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million. It is characterized by hemolysis, bone marrow dysfunction with peripheral blood cytopenia, hypercoagulability, thrombosis, renal impairment and arterial and pulmonary hypertension. Hemolysis and subsequent hemosider…

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease that presents an estimated incidence of 1.3 cases per million per year, with a prevalence of 15.9 cases per million. It is characterized by hemolysis, bone marrow dysfunction with peripheral blood cytopenia, hypercoagulability, thrombosis, renal impairment and arterial and pulmonary hypertension. Hemolysis and subsequent hemosiderin accumulation in tubular epithelium cells induce tubular atrophy and interstitial fibrosis. The origin of PNH is the somatic mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene located on Xp22: this condition leads to the production of clonal blood cells with a deficiency in those surface proteins that protect against the lytic action of the activated complement system. Despite the increased knowledge of this syndrome, therapies for PNH were still only experimental and symptomatic, until the introduction of the C5 complement blockade agent Eculizumab. A second generation of anti-complement agents is currently under investigation, representing future promising therapeutic strategies for patients affected by PNH. In the case of chronic hemolysis and renal iron deposition, a multidisciplinary approach should be considered to avoid or treat acute tubular injury or acute kidney injury (AKI). New promising perspectives derive from complement inhibitors and iron chelators, as well as more invasive treatments such as immunoadsorption or the use of dedicated hemodialysis filters in the presence of AKI.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder that manifests with bone marrow failure, thrombosis and hemolysis. We present a 28-year-old male who presented with weakness, jaundice and transfusion dependence. On initial investigation, he was found to have anemia with jaundice with hemoglobin (Hb) capillary zone electrophoresis suggestive of Hb E (HBB: c.79G>A) trait. Th…

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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder that manifests with bone marrow failure, thrombosis and hemolysis. We present a 28-year-old male who presented with weakness, jaundice and transfusion dependence. On initial investigation, he was found to have anemia with jaundice with hemoglobin (Hb) capillary zone electrophoresis suggestive of Hb E (HBB: c.79G>A) trait. The same anomaly was also found in his mother. However, transfusion requirement was an unusual feature in the patient. As his corrected reticulocyte count was raised along with lactate dehydrogenase (LDH), which was suggestive of a hemolytic process, he was worked-up for the same. However, the direct Coombs test was negative. A bone marrow aspiration and biopsy was done to rule out hypersplenism but it revealed erythroid hyperplasia with reduced iron stores despite normal ferritin and iron studies. This was unusual as the patient had anemia requiring transfusions. He had no history of hemoglobinuria but a PNH by flowcytomety revealed a large clone of 81.2% in granulocytes and 88.5% in monocytes. The patient was started on Danazol and steroids for anemia which improved. He was counseled for matched sibling stem cell transplant. He had a full match with his brother. At the time of this study he awaits his transplant.

Haptoglobin (Hp) is a plasma glycoprotein that scavenges cell-free hemoglobin (Hb). Hp has various potential therapeutic applications, but it has been mainly studied for treatment of acute hemolytic conditions that can arise from situations such as massive blood transfusion, infusion of stored red blood cells, severe burns, trauma, sepsis, radiation injury, and others. Therefore, Hp may also be b…

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Haptoglobin (Hp) is a plasma glycoprotein that scavenges cell-free hemoglobin (Hb). Hp has various potential therapeutic applications, but it has been mainly studied for treatment of acute hemolytic conditions that can arise from situations such as massive blood transfusion, infusion of stored red blood cells, severe burns, trauma, sepsis, radiation injury, and others. Therefore, Hp may also be beneficial during chronic hemolytic disease states such as hereditary spherocytosis, nocturnal hemoglobinuria, sickle-cell anemia, and malaria. Various methods have been developed to purify Hp from plasma or plasma fractions. However, none of these methods have exploited the large molecular weight (MW) range distribution of Hp polymers to easily isolate Hp from other plasma proteins. The present study used tangential flow filtration (TFF) to isolate polymeric Hp from plasma proteins using human Fraction IV (FIV) as the starting material. After removal of insoluble material from a suspension of FIV paste, the protein mixture was clarified on a 0.2 μm hollow fiber (HF) TFF filter. The clarified protein solution was then bracketed based on protein MW using HF filters with MW cut-offs (MWCOs) of 750, 500, and 100 kDa. Using untreated FIV, the Hp purity of the main bracket was ~75% with a total Hb binding capacity (HbBC) yield of 1.2 g starting from 500 g of FIV paste. However, pretreatment of FIV with fumed silica to remove lipoproteins increased Hp purity to >95% with a HbBC yield of 1.7 g per 500 g of FIV. Taken together this study provides a novel and scalable method to purify Hp from plasma or plasma fractions.

Complement is a part of the innate immune system with a critical role in host defense. Although essential for survival, when dysregulated or excessively triggered complement activation can cause tissue damage and drive inflammatory and immune disorders. The alternative pathway of complement (APC) is especially important for survival against infection and can be triggered by a variety of settings:…

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Complement is a part of the innate immune system with a critical role in host defense. Although essential for survival, when dysregulated or excessively triggered complement activation can cause tissue damage and drive inflammatory and immune disorders. The alternative pathway of complement (APC) is especially important for survival against infection and can be triggered by a variety of settings: infection, trauma, surgery, or pregnancy. This excessive drive of complement manifest distinctive hemolytic diseases like atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH). These diseases share phenotypic similarities to HELLP syndrome: a hypertensive disorder of pregnancy with hemolysis, elevated liver enzymes, and low platelets. In this manuscript, there will be a brief review of complement activation and a description of important regulator proteins. The review will further discuss pregnancy as a major trigger of the alternative pathway, and how diseases of the APC are treated during pregnancy. Finally, the similarities between HELLP syndrome and diseases of the APC will be examined.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement-mediated intravascular hemolysis and thrombosis. The increased incidence of PNH-driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement-mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to s…

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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement-mediated intravascular hemolysis and thrombosis. The increased incidence of PNH-driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement-mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti-thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in-part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure.

The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP…

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The renaissance of complement diagnostics and therapeutics has introduced precision medicine into a widened field of complement-mediated diseases. In particular, complement-mediated diseases (or complementopathies) with ongoing or published clinical trials of complement inhibitors include paroxysmal nocturnal hemoglobinuria, cold agglutinin disease, hemolytic uremic syndrome, nephropathies, HELLP syndrome, transplant-associated thrombotic microangiopathy, antiphospholipid antibody syndrome, myasthenia gravis, and neuromyelitis optica. Recognizing that this field is rapidly expanding, we aim to provide a state-of-the-art review of (a) current understanding of complement biology for the clinician, (b) novel insights into complement with potential applicability to clinical practice, (c) complement in disease across various disciplines (hematology, nephrology, obstetrics, transplantation, rheumatology, and neurology), and (d) the potential future of precision medicine. Better understanding of complement diagnostics and therapeutics will not only facilitate physicians treating patients in clinical practice but also provide the basis for future research toward precision medicine in this field.

CONCLUSIONS: The PNH-PPQ provides a patient-centered approach for evaluating preferences for the treatment of PNH. The PNH-PPQ has subsequently assessed patient preference in the clinical trial sub-study ALXN1210-PNH-302s.

Leptospirosis is a transmissible zoonotic disease caused by pathogenic strains of the genus Leptospira. Clinical signs in cattle are fever, haematuria, haemoglobinuria, meningitis, abortion, birth of weak calves and infertility; in the most severe cases, it can cause death to the animal. The few studies conducted in Ecuador, and in particular the province of Manabí, have revealed varying prevalen…

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Leptospirosis is a transmissible zoonotic disease caused by pathogenic strains of the genus Leptospira. Clinical signs in cattle are fever, haematuria, haemoglobinuria, meningitis, abortion, birth of weak calves and infertility; in the most severe cases, it can cause death to the animal. The few studies conducted in Ecuador, and in particular the province of Manabí, have revealed varying prevalence rates, ranging from 35.8% to 75%. The objective of this study is to determine the seroprevalence of leptospirosis in cattle and to ascertain the main serovars circulating in the province of Manabí. A cross-sectional epidemiological study was conducted from November 2015 to March 2016, for which seven cantons were selected at random and a total of 854 animals from 67 herds were investigated. The samples were processed in the laboratories of the Animal Diagnostics Directorate of the Ecuadorian Agency for Agriculture Quality Assurance (AGROCALIDAD) in Tumbaco, using the microscopic agglutination test. The sera were analysed to check whether they contained any of the eight serovars of Leptospira interrogans circulating most frequently in the country: Canicola, Hardjo, Pomona, Icterohaemorrhagiae, Grippotyphosa, Wolffi, Bratislava and Copenhageni. Overall seroprevalence at herd level was 97.01%, with the most common serovars being Pomona, Icterohaemorrhagiae, Grippotyphosa, Bratislava and Canicola. It was concluded that there is high seroprevalence at herd level in the province of Manabí.

Autoimmune haemolytic anaemia (AIHA) and paroxysmal nocturnal haemoglobinuria (PNH) are two distinct causes of haemolytic anaemia. They have different mechanisms that underpin their pathogenesis and, therefore, require different treatment strategies. The direct antiglobulin test (DAT) or Coombs test is positive in cases of immune-mediated haemolytic anaemia and, thus, is positive in AIHA but nega…

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Autoimmune haemolytic anaemia (AIHA) and paroxysmal nocturnal haemoglobinuria (PNH) are two distinct causes of haemolytic anaemia. They have different mechanisms that underpin their pathogenesis and, therefore, require different treatment strategies. The direct antiglobulin test (DAT) or Coombs test is positive in cases of immune-mediated haemolytic anaemia and, thus, is positive in AIHA but negative in PNH. We report a case of a woman presenting with a haemolytic anaemia who was found to have concomitant evidence of AIHA and PNH. The case highlights the importance of carrying out a comprehensive haemolysis work-up in patients who present with haemolytic anaemia.

Acquired aplastic anemia (AA) is a rare hematological disease characterized by bone marrow hypocellularity and varying degrees of pancytopenia. Immunosuppressive therapy (IST) is currently one of the first-line treatments for AA; however, unresponsiveness remains a major concern. Although previous studies have suggested several common risk factors for unresponsiveness, there are currently no wide…

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Acquired aplastic anemia (AA) is a rare hematological disease characterized by bone marrow hypocellularity and varying degrees of pancytopenia. Immunosuppressive therapy (IST) is currently one of the first-line treatments for AA; however, unresponsiveness remains a major concern. Although previous studies have suggested several common risk factors for unresponsiveness, there are currently no widely accepted predictors. Therefore, a meta-analysis of clinical trials including information on factors associated with unresponsiveness of AA to IST was performed in the present study. The PubMed, Embase and Cochrane Library databases were searched for clinical studies on AA evaluating the association between risk factors and unresponsiveness to IST. After the factors were defined from the selected studies, the association between these factors and unresponsiveness to IST was analyzed using Review Manager software. A total of 10 studies comprising 1,820 cases were included in the present meta-analysis. The following factors were identified as predictors of unresponsiveness: Age (≥60 years), sex, absolute neutrophil count, severity of the disease, paroxysmal nocturnal hemoglobinuria clone, human leukocyte antigen (HLA)-DR2 and cytogenetic abnormalities (CAs). Among these factors, only age (≥60 years) [odds ratio (OR)=1.65], HLA-DR2 negativity (OR=2.72) and CAs (OR=1.93) exhibited a statistically significant association with unresponsiveness to IST (P=0.006, P=0.04 and P=0.01, respectively). In conclusion, the present meta-analysis revealed that age ≥60 years, HLA-DR2 negativity and CAs are risk factors for unresponsiveness to IST. This result may enable clinicians to select an effective therapeutic scheme for patients with AA and even provide novel clues to the pathogenesis of AA.

Paroxysmal cold hemoglobinuria is a rare form of autoimmune hemolytic anemia caused by the Donath-Landsteiner autoantibody. The condition is characterized by the presence of an IgG biphasic hemolysin with specificity to the P blood group antigen. The antibody biphasic action may be demonstrated in the Donath-Landsteiner test. While paroxysmal cold hemoglobinuria can be manifested at any age, it t…

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Paroxysmal cold hemoglobinuria is a rare form of autoimmune hemolytic anemia caused by the Donath-Landsteiner autoantibody. The condition is characterized by the presence of an IgG biphasic hemolysin with specificity to the P blood group antigen. The antibody biphasic action may be demonstrated in the Donath-Landsteiner test. While paroxysmal cold hemoglobinuria can be manifested at any age, it typically appears in children following a viral upper respiratory syndrome or immunization, though rarely. This report describes a 23-months old girl presented with 5 days history of fever, erythrocytopenia, leukocytosis and occurrence of dark urine. On admission, the physical examination showed pallor, no scleral icterus, a mild hyperemic throat and no hepatosplenomegaly. The investigations revealed severe anemia with hemoglobin of 44g/L, increased reticulocyte count (10.67%), elevated lactate dehydrogenase (2603IU/L), decreased serum haptoglobin (0.159g/L), normal G6PD. Direct antiglobulin test was positive with C3d and C3c complement components only. Direct and indirect Donath-Landsteiner tests were positive. The girl was treated with a intravenous immunoglobulin infusion and Cefotaxime. She received transfusion of red blood cells, crossmatched, although P antigen untyped. Despite this in vitro serological incompatibility she had a hemoglobin increase. The patient was discharged in stable condition on the seventh day following admission. Paroxysmal cold hemoglobinuria is a hemolytic anemia for which a specific diagnostic test is available. Timely recognition of the disease by pediatricians is crucial as well as the highly skilled hospital blood bank staff performing Donath-Landsteiner testing.

Although Heme Oxygenase-1 (HO-1) induction in various forms of kidney injury is protective, its role in age-related renal pathology is unknown. In the ageing kidney there is nephron loss and lesions of focal glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriolosclerosis. Underlying mechanisms include podocyte (visceral glomerular epithelial cell/GEC) injury. To assess whether H…

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Although Heme Oxygenase-1 (HO-1) induction in various forms of kidney injury is protective, its role in age-related renal pathology is unknown. In the ageing kidney there is nephron loss and lesions of focal glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriolosclerosis. Underlying mechanisms include podocyte (visceral glomerular epithelial cell/GEC) injury. To assess whether HO-1 can attenuate ageing - related lesions, rats with GEC-targeted HO-1 overexpression (GECHO-1 rats) were generated using a Sleeping Beauty (SB) transposon system and extent of lesions over a 12-month period were assessed and compared to those in age-matched wild-type (WT) controls. GECHO-1 rats older than 6 months developed albuminuria that was detectable at 6 months and became significantly higher compared to age-matched WT controls at 12 months. In GECHO-1 rats, lesions of focal segmental and global glomerulosclerosis as well as tubulointerstitial lesions were prominent while podocytes were edematous with areas of foot process effacement and glomerular basement membrane thickening and wrinkling. GECHO-1 rats also developed hemoglobinuria and hemosiderinuria associated with marked tubular hemosiderin deposition and HO-1 induction, while there was depletion of splenic iron stores. Kidney injury was of sufficient magnitude to increase serum lactate dehydrogenase (LDH) and was oxidative in nature as shown by increased expression of 8-hydroxydeoxyguanosine (8-OHdg, a byproduct of oxidative DNA damage) in podocytes and tubular epithelial cells. These observations highlight a detrimental effect of podocyte-targeted HO-1 overexpression on ageing-related renal pathology and point to increased renal iron deposition as a putative underlying mechanism.

CONCLUSIONS: In ravulizumab-treated PNH patients, IgG and IgG subclass levels which are regulated by the FcRn remained unaffected. Therefore, no treatment associated hypogammaglobulinemia is to be feared under chronic ravulizumab therapy.